Azithromycin is the U.S.A.N. (generic name) for 9a-aza-9a-methyl-9-deoxo-9a-homoerythromycin A, a broad spectrum antimicrobial compound derived from erythromycin A. Azithromycin was independently discovered by Bright, U.S. Pat. No. 4,474,768 and Kobrehel et al., U.S. Pat. No. 4,517,359. These patents disclose that azithromycin and certain derivatives thereof possess antibacterial properties and are accordingly useful as antibiotics. Azithromycin may be made, formulated and administered according to procedures described in the following U.S. patents, which are all incorporated herein in their entirety by reference: U.S. Pat. Nos. 6,268,489; 4,963,531; 5,633,006; 5,686,587; 5,605,889; 6,068,859; 4,328,334; and 5,498,699.
Azithromycin is administered for the treatment of infections, particularly respiratory infections, more particularly respiratory infections of the bronchial tract, lungs, and sinus, and still more particularly acute otitis media. Acute otitis media is an inflammation of the area behind the eardrum (tympanic membrane) in the chamber called the middle ear. Acute otitis media is an infection that produces pus, fluid, and inflammation within the middle ear.
Acute otitis media may be caused by a variety of pathogens, such as M. catarrhalis, S. pneumoniae, and H. influenzae. Acute otitis media is particularly common in infants and children. Azithromycin has been prescribed for the treatment of acute otitis media with a 30 mg/kg body weight total treatment dose given as a five day regimen in the US and as a three day regimen in Europe. The multiple dosages prescribed to completely cure the infection have caused compliance problems, particularly in pediatric patients. Even in the adult population, compliance with multiple dosaging regimens is not complete because of forgetfulness and other reasons. A method of treating and curing infection, particularly a microbial infection such as acute otitis media, by administering a single dose of azithromycin would significantly shorten courses of therapy and be of a great advantage to patient compliance.
A continual problem with antibiotic therapy is the emergence of resistant microbial strains. A method of treating microbial infections with a reduced risk of developing treatment-resistant strains is desirable. It is believed that a single dose azithromycin treatment provides such as reduced risk. The inflammatory cells provide a mode of transport of azithromycin to the infection site and provide a reservoir for azithromycin at the infection site. As a result, azithromycin is characterized by high and sustained concentrations in a wide range of tissues, and a particularly increased concentration at sites of infection. It is believed that a single dose therapy with azithromycin, by providing a higher initial concentration at the infection site, may help prevent less susceptible sub-populations of the pathogens initially present from becoming established. Also, a single-dose regimen will result in greater patient compliance, which should contribute to reduced emergence of less susceptible strains.
A related resistance problem is the problem of treating infection caused by pathogens having a high susceptibility threshold to most therapeutically available antiinfective agents. Such resistant pathogens are characterized by being unlikely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable and other therapy is needed. Often, the other therapy involves anti-infective agents with undesirable side effects, such as severe gastrointestinal distress or heightened sensitivity to sun. It is an ongoing problem to develop new therapies to treat disorders caused by such pathogens that exhibit resistance to available anti-infective agents while minimizing undesirable side-effects. It is an object of the present invention to solve these problems with a well-tolerated therapy of a sufficient dosage of azithromycin administered as a single dose to treat infections caused by certain resistant pathogens.
Single dose administration of azithromycin for the treatment of non-gonococcal urethritis and cervicitis due to C. trachomatis has been prescribed and is a therapy approved by the US Food and Drug Administration. Single dose treatment of respiratory infections in humans with azithromycin has been reported. For example, Stan Block et al. reported on a study in which a single dose of azithromycin (30 mg/kg) was administered to treat acute otitis media in infants and children six months to twelve years of age. S. Block et al., “Single-Dose Azithromycin (30 mg/kg) in Acute Otitis Media”, 38th Annual Meeting of the Infectious Diseases Society of America, New Orleans La., Sept. 7–10, 2000 [Abstract 174]. Arguedas reported on single-dose therapy in otitis media using azithromycin in infants and children. Arguedas, A., “Single-dose therapy in otitis media”, Poster Presentation at 9th European Congress of Clinical Microbiology and Infectious Diseases, Berlin, Germany, Mar. 21–24, 1999, Clin. Microbiol. Infect. 1999:5 (Supp. 3 March):28 (Abstr). A single oral dose of 2 g azithromycin was administered to healthy male subjects in tests of gastrointestinal side effects reported in U.S. Pat. No. 6,068,859.